Anticoagulants are useful therapeutic agents in the pharmacological treatment of, for example, acute deep venous thrombosis, pulmonary embolism, acute arterial embolization of the extremities, myocardial infarction, and disseminated intravascular coagulation. Prophylactic administration of anticoagulants is believed to prevent a recurrence of embolism in patients with rheumatic or arteriosclerotic heart disease and to prevent certain thromboembolic complications of surgery. Administration of anticoagulants has also been indicated in the treatment of coronary artery and cerebrovascular disease. Arterial thrombosis, particularly in arteries supplying the heart muscle and brain, is a leading cause of death.
Hirudin is a 65 residue polypeptide isolated from the salivary glands of leeches. It is an anticoagulant agent, which is a thrombin specific inhibitor. Although quite potent, clinical use of hirudin isolated from leech extracts seems unlikely because of its limited quantity, expense, and allergic reactions which commonly follow administration of any foreign protein of this size.
Originally, applicants discovered a specific region of hirudin that is responsible, at least in part, for its anticoagulant activity . The peptide region (amino acid 55 to 65 of Hirudin) was chemically synthesized and shown to bind the recognition site of thrombin; the recognition site being spatially distinct from the the enzymatic cleavage site. Binding of synthetic peptides were also shown to competitively prevent binding of fibrinogen to the recognition site of thrombin, an important prerequisite to fibrin production and clot formation, and are thereby of potential medical value as anticoagulants.
Applicants have further prepared derivatives of this peptide containing single amino acid deletions of the basic sequence. Specifically, this series of amino acid deletions, taken in total, define the extent of sequence dependency of the peptide, positionally and compositionally, and provide the basis for extended rational drug design. Many of the peptide analogs of this type have attributes of the parent peptide and therefore may also serve as a scientifically interesting and therapeutically significant adjunct to anticoagulant therapy. Moreover, the amino acid analogs may in themselves contain enhanced potency and extended duration of action.